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Cardiac Glycosides

PHM142 Fall 2012 Instructor: Dr. Jeffrey Henderson. Cardiac Glycosides . October 17, 2012 Sarah Johnson Maya Hamam Barret Barr Divya Prajapati. What are Cardiac Glycosides? . Family of compounds derived from the Digitalis plant ( Digitalis purpurea or Digitalis lanata ) .

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Cardiac Glycosides

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  1. PHM142 Fall 2012 Instructor: Dr. Jeffrey Henderson Cardiac Glycosides October 17, 2012 Sarah Johnson Maya Hamam Barret Barr Divya Prajapati

  2. What are Cardiac Glycosides? Family of compounds derived from the Digitalis plant (Digitalis purpurea or Digitalis lanata)

  3. What are Cardiac Glycosides? Contain a polysaccharide chain, a steroid portion and a lactone ring

  4. Types Two main types: Bufadienolides and Cardenolides

  5. What are they used for? Cardiac glycosides are cardiotonic drugs Used in the treatment of congestive heart failure and cardiac arrhythmia

  6. Digitoxin

  7. Digoxin Also known as Lanoxin

  8. Starling Curve Increase contractile strength of failing heart by 50-100% Drugs have little effect on a healthy heart Decompensation  contractions get weaker In heart failure: - Decompensation occurs well below the pericardium limit Why use Cardiac Glycosides?

  9. Mechanism of Action • Digitalis acts on Na+/K+ ATPase to inhibit it • Keeping the pump phosphorylated state

  10. Mechanism of Action • Partial Inhibition of Na+/K+ ATPase • Electrochemical driving force for Na+ disappears • CICR from SR • Result: - Increase in the strength of contraction

  11. Signs: Biphasic / inversions of T-wave in ECG Uneven depolarization in parts of the ventricle Toxicity- Digitalis Overdose

  12. Adverse Reactions of Digoxin • Cardiac Related Adverse Effects • Gastrointestinal Related Adverse Effects • Central Nervous System Related Adverse Effects

  13. Tx for Adverse Reactions • Removal from drug therapy • Pacemaker • DIGIBIND

  14. Quinidine Itraconazole Propafenone Verapamil Amiodarone Indomethacin Inhibits P-glycoprotein mediated glycoside transporter in the kidney Digitalis clearance is decreased and bioavailability is increased Serum levels of Digitalis can reach potentially toxic concentrations Drug-Drug Interactions

  15. Antibiotics: Azithromycin Telithromycin Erythromycin Clarithromycin Tetracycline Decreased renal clearance and increased bioavailability due to P-glycoprotein inhibition Destruction of gut bacteria capable of metabolizing Digitalis Inhibition of CYP3a4 metabolism in liver All 3 mechanisms increase Digitalis serum levels to potentially toxic concentrations Drug- Drug Interactions

  16. Cardiac glycosides are a family of compounds derived from the digitalis plant Digitalis consists of two major cardiac glycosides: Digitoxin and Digoxin. Cardiac Glycosides partially inhibit the E2 Na+/K+ ATPase by preventing dephosphorylation. This causes Na+ to accumulate inside the cell, inhibiting NCX and causes VOCC to open. The rise in Ca+2 induces SR to release Ca+2 which results in a stronger contraction of the ventricle. Overdose results in complete inhibition of the Na+/K+ pump no membrane repolarization no muscle relaxation heart stops beating! Adverse reactions of Digoxin normally only occur at doses higher than those needed to achieve a therapeutic effects. Massive overdoses of Digoxin can be reversed using DIGIBIND, a drug that binds to Digoxin molecules making them unavailable for biding at their site of action in the body There are three main mechanisms that can make Digitalis concentrations potentially toxic. 1) inhibition of P-glycoprotein transporter in the kidneys 2) eradication of gut bacteria that metabolize Digitalis 3) inhibition of Cyp3A metabolism in the liver. Summary

  17. eCPS Guyton, A.C. and J.E. Hall. 2006. Electrocardiographic Interpretation of Cardiac Muscle and Coronary Blood Flow Abnormalities: Vectorial Analysis., p. 146, 261-263. In W. Schmitt and R. Gruliow, Textbook of Medical Physiology, Elsevier Saunders, Philadelphia. Schwartz, A., Whitner, K., Grupp, G., Grupp, I., Adams, R., and S. Lee. 1982. Mechanism of Action Digitalis: Is the Na,K-ATPase The Pharmacological Receptor?. Annals New York Academy of Sciences, 82, 253-271. Winnicka K., Belawski K., Bielawska A., 2006. Cardiac Glycosides in Cancer Research and Cancer Therapy. Acta Poloniae Pharmaceutica n Drug Research. Vol. 63 No. 2 pp. 109-115 Wood, C. and C. Nurse. 2011. Bio 3U03 Animal Physiology:Homeostasis– Term I. Cardiac Physiology., Lecture 5 p. 4. McMaster Uni. References

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